the larger cations tetramethylammonium, tetraethylammonium, or N-methyl-D-glucamine (Figure 1E). This size-selective permeability increase is characteristic of claudin-2 channel activity (14-16, 48-50), but does not exclude the possibility that other cation-selective pore-forming claudins, e.g., claudin-15 (10, 13, 22), contribute to IL-13-induced barrier loss in vivo. We therefore asked if claudin-2 was required for IL-13-induced barrier loss. Prior to IL-13 treatment, paracellular permeability was similar in Cldn2 +/+ and Cldn2-/mice, consistent with limited claudin-2 expression in adults. IL-13 treatment was not, however, able to increase paracellular permeability of small cations, including Na + and methylamine in Cldn2-/mice (Figure 1F). Claudin-2 is therefore necessary for IL-13-induced increases in intestinal pore pathway permeability. In order to determine if claudin-2 upregulation is sufficient to mediate the effects of IL-13 on intestinal cation permeability, transgenic mice expressing GFP-tagged mouse claudin-2 from the intestinal epithelium-specific villin (Vil1) promoter (Cldn2 Tg) were characterized (29). Total claudin-2 expression (the sum of endogenous and GFP-claudin-2) in these Cldn2 Tg mice was similar in distribution (Figure 1G) to that of IL-13-treated Cldn2 +/+ mice (Figure 1B) and increased 3.3-fold relative to Cldn2 +/+ mice that did not receive IL-13 (Figure 1, H and I). Moreover, transgenic GFPclaudin-2 expression selectively increased paracellular permeability of Na + , methylamine, and, to a lesser extent, ethylamine, in a manner that recapitulated the effect of IL-13 on Cldn2 +/+ mice (Figure 1J). Claudin-2 is, therefore, both necessary and sufficient to mediate IL-13-induced barrier loss in vivo. Transgenic claudin-2 expression exacerbates immune-mediated colitis. We have found that severity and duration of infectious colitis are reduced in these GFP-Cldn2 Tg mice (29). A study of similar transgenic mice expressing human claudin-2 from the same Vil1 promoter demonstrated that claudin-2 overexpression was also protective in DSS-induced, chemical colitis (41). Conversely, claudin-2 knockout exacerbated infectious and chemical colitis (29, 42). These data suggest that claudin-2-mediated pore pathway permeability increases may be adaptive, i.e., beneficial in IBD. To test this hypothesis, we compared severity of experimental IBD in immunodeficient Cldn2 Tg Rag1-/and Cldn2 +/+ Rag1-/mice using the well-established T cell transfer model (33, 51). Unexpectedly, disease was significantly more severe in Cldn2 Tg Rag1-/mice relative to Cldn2 +/+ Rag1-/mice. This was demonstrated by more extensive weight loss (Figure 2A) and greater disease activity (Figure 2B). Consistent with increased disease severity, leak (macromolecular) and unrestricted (epithelial damage) pathway permeabilities, measured as 4-kDa and 70-kDa dextran flux, respectively, were markedly greater in Cldn2 Tg Rag1-/mice relative to Cldn2 +/+ Rag1-/mice (Figure 2C and ref. 29). Colitis was associated with increased claudin-2 exp...

VDZ is similarly effective in ant-TNF-naïve CD and UC patients. The efficacy is higher than reported in anti-TNF-experienced patients and is comparable to that of anti-TNF biologics in this population.

No abstract

Solutions and emulsions of sodium or potassium salts in a series of saturated fatty acids from C₈ to C₁₈ were given in a dose of 0.5 g intraduodenally to healthy males or patients with healed duodenal ulcer. A double-lumen Sarles tube with a balloon placed in the proximal duodenum was used. The substances were instilled after a plateau of gastric acid secretion induced by a continuous infusion of pentagastrin was reached. In order to exclude unspecific effects, the test solutions were adjusted to a pH around 7.0 and to plasma isosmolality. Compared with the other tested substances, the emulsion of 0.5 g sodium-oleate was the most effective in inhibiting the stimulated gastric acid secretion. Sodium caprinate and caprylate had a considerable, but smaller effect than oleic acid on the secretory plateau. Palmitate and laurate provoked only a slight decrease in acid secretion. Myristate was ineffective. These results could suggest that different receptors are responsible’ for fat-induced inhibition of the gastric acid secretion.